immuno Flashcards
1
Q
Important gene in DiGeorges syndrome?
A
TBX1 gene
2
Q
DiGeorge syndrome is also known as….
A
22q11.2 microdeletion
3
Q
What pathogens do NK cells attack?
A
Intracellular pathogens (via downregulation of HLA-1 proteins on the surface)
4
Q
Types of secondary immunodeficiencies
A
Malignancy - leukemia, lymphoma, myeloma
Drugs - steriods, cytotoxic drugs and immunosuppresants
Infection - HIV, measles, mycobacteria
Biochemical disorders - chronic renal failure, malnutrition
5
Q
Hx of immunodeficiency
A
Family histroy Chronic diarrhoea Recurrent infections Failure to thrive Mouth ulcers Skin rashes
6
Q
What kind of infections do patients with IgA deficiency get?
A
Resp and GI infections
7
Q
Who is at risk of getting IgA deficiency ?
A
Burns patients
8
Q
What is PRR and what does it detect?
A
Innate immune system - Pathogen recognition receptors
Detects PAMPs
9
Q
What can cells of the innate immune system secrete to help them regulate their immuneresponse?
A
Chemokines
Cytokines
10
Q
Which cells are polymorphonuclear cells?
A
Basophils
Eosinophils
Neutrophils
11
Q
Where are polymorphonuclear cells made?
A
Bone marrow
12
Q
Role of polymorphonuclear cells?
A
Phagocytosis
Oxidative and non-oxidative killing
Release enzymes into granules
Express PRR and secrete cytokines and chemokines
13
Q
What does infection cause the endothelium to do?
A
Expression adhesion molecules
14
Q
What happens if there is a deficiency in macrophages
A
Recurrent infections in mouth and skin
Deep infections
15
Q
What is an opsonins?
A
Coats pathogen to help with its recognition and clearance
16
Q
Why does phagocytosis kill neutrophils?
A
Depletes them of their glycogen reserves and leads to apoptosis
17
Q
What is oxidative killing?
A
NADPH oxidase complex converts oxygen into a reactive oxygen species - superoxide and hydrogen peroxide
Myeloperoxidase catalyses production of hydrochlorous acid from hydrogen peroxide and chloride;
hydrochlorous acid is a highly effective oxidant and anti-microbia
18
Q
What is non-oxidative killing?
A
Use of bactericidal enzymes - lysozyme and lactoferrin into the phagolysome
19
Q
What are the primary defects of phagocytes in primary immunodecifiency? More deets on next cards
A
- Issues to produce neutrophils
- Issues with migration of neutrophils
- Issues with endocytosis (eating) of pathogens
- Issues with formation of the phagolysome
- Issues with killing - oxidative and non-oxidative
- Issues with recruiting other cells during the killing process
20
Q
What conditions lead to issues with recruitment (producing neutrophils)?
A
- Reticular dysgenesis - failure of stems to differentiate along myeloid or lymphoid lineage due to mitochondrial mutation
- Kostmann’s syndrome - autosomal recessive congenital condition which leads to severe neutropenia
- Cyclic neutropenia - autosomal dominant condition leading to episodes of neutropenia every 4-6 weeks due to defect in ELA-2 (neutrophil elastase)
21
Q
What conditions leads to issues with migration of neutrophils?
A
- Leukocyte adhesion deficiency: due to issue with CD18 receptor usually found on the neutrophil surface. CD18 is used to bind to the surface of endothelium cells to regulate neutrophil adhesion. If this fails, neutrophils stay in the blood and can’t enter tissue
Patients tend to have a high neutrophil count but no abscess or pus formation
think LAD 18
22
Q
What conditions leads to issues with endocytosis and formation of the phagolysosome?
A
Issues with complement or antibody formation will compromise opsonisation so making it harder to eat the pathogen
23
Q
What condition leads to issues with killing - oxidative and non-oxidative?
A
Chronic granulatamous disease - failure of oxidative killing due to mutation of NADPH oxidase complex so it cant make reactive oxygen species/oxygen free radicals. Failure to breakdown intracellular pathogen
Patient will have constant inflammation, formation of granulomas, lymphadenopathy and hepatosplenomegaly
24
Q
How to Ix chronic granulatamous disease?
A
Nitroblue tetrazolium test - which is supposed to change from yellow to blue in the presense of hydrogen peroxide
Dihydro-rhodamine (DHR) flow cytometry test
25
What conditions leads to issues with recruitment of other cells of the immune system?
Issue with IFN-gamma and IL-12. Infection with MYCOBACTERIA causes IL-12 to induce T-cells to produce IFN-gamma. This stimulates macrophages and neutrophils and stimualtes oxidative pathways
Patients with this condition are suspectible to mycobacteria infection
26
What kind of infections would we worry about in NK cell deficiency?
Viral infections especially herpes virus
27
What types of NK cell deficiency are there?
Classical - lack of NK cells (GATA2 and MCM4)
| Functional - abnormal functioning NK cells (FCGR3A gene)
28
Tx of NK cell deficiency
Prophylaxis with aciclovir, gangclovir
Cytokines with INF-alpha can be used to stimulate NK cells cytotoxicity
Haematopoietic stem cell transplantation
29
Where is complement made?
Liver
30
Different pathways involved with complement cascade
Classical : C1, C2, C4. Activated by antigen-antibody complexes
Alternative - directly triggered by C3 to bacterial cell wall
Mannon binding lectin - C2 and C4. Activates classical pathway
31
Whats the most important part of the complement cascade
C3 - amplication of the complement cascade and triggers the formation of the MAC (membrane attack complex) via C5-C9.
32
Which pathogens are people with a complement deficiency more at risk to?
Encapsulated organisms: N.mengitiditis, h.influenzae, s.pneumoniae
SLE patients are at risk if earlier components of complement cascade involved
33
Which complement deficiency is associated with SLE?
C2 and mainly the classical pathway complement proteins
| Failure to clear necrotic cells - autoimmunity risk?
34
Mannan binding lectin pathway deficiency?
MBL deficiency is relatively common, with 10% having no MBL. It is associated with increased infection in patients with another cause of immune impairment, e.g.
premature infants, chemotherapy patients, HIV patients, and antibody deficiency
patients.
35
What happens if there are defects in the aternative pathway?
If there are defects in the alternative pathway, there is an inability to mobilise complement rapidly in response to bacterial infections, and there will be recurrent infection with encapsulated bacteria. It is very rare – factor B, I and P deficiency can all occur.
36
What is there is a C3 deficiency?
leads to severe susceptibility to infection from bacteria, and an increased risk of development of connective tissue disease. A defect in the terminal common pathway results in an inability to make membrane attack complexes or use complement to lyse encapsulated bacteria. It results in a very specific hole in the immune system, leading to opportunistic infections by Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae.
37
Cause of secondary complement deficiency?
Glomerulonephritis
38
Ix complement deficiency?
blood samples measuring C1 and C4
39
What do T-cells express on their surface?
CD3, CD4 or CD8
40
How do T-cells communicate with immune cells from the innate immune system?
APC via HLA molecule complex
41
CD4 has an affinity for which HLA complex?
HLA-II
42
CD8 has an affinity for which HLA complex?
HLA-I
43
Role of TH1
Helps CD8 T cells and macrophages
44
Role of TH17
Helps neutrophil recruitment
45
Role of Treg
IL-10/TGF beta expressing?
46
How is CD8 cytotoxic?
Perforin, granzymes and expression of FAS ligand which binds to fats and causes apoptosis
47
Patients with T-cell deficiency are more at risk of getting what kind of infections?
Viral infections - CMV
Some fungal
Some bacterial
Early malignancy
48
Patients with B-cell/antibody deficiency are more at risk of getting what kind of infections?
Bacterial infections
Toxins - diptheria
Some viral
49
Why do babies with SCID present after 3 months?
Maternal immunoglobulin protection (active transport of IgG across the placenta)
50
More on reticular dysgenesis
SCID
Failure to differentiate lymphoid and myeloid lineage so you dont make lymphocytes, macrophages, neutrophils and platelets
Mutation - in mitochondrial energy
metabolism enzyme Adenylate Kinase 2 (AK2)
Fatal unless haematopoetic stem cell transplantation
51
X-lined SCID
Mutation of the gamma chain of IL-2 receptor
| Causes inability to respond to cytokines and produce mature B-cells
52
DiGeorge syndrome
```
Mutation on chromosome 22 (22q11.2)
Thymic hypoplasia
Hypocalcemia
B-cells normal
T-cell reduced
```
53
Bare lymphocyte syndrome
This is a defect in one of the regulatory proteins
involved in Class II gene expression, typically regulatory factor X or Class II Transactivator.
There is an absent expression of MHC Class II molecules, leading to a profound deficiency of CD4+ cells, but a normal number of CD8+ cells.
There will be a normal number of B cells, but a failure to make IgG or IgA antibodies. BLS I also exists, which is a failure to express HLA Class I. These children normally become unwell at 3 months, with infections of all types and failure to thrive.
54
Cytokine deficiencies
IL-12 and IFN-gamma = mycobacterial infection susceptiblity
55
Risk of IL12 and IFN-gamma deficiency
Mycoplasma infection
Infection after BCG vaccine
Salmonella
Unable to form granulomas
56
Bruton's Agammaglobulinaemia
X-linked tyrosine kinase defect
BTK gene mutation
Issue making mature B-cells
Symptoms occur 3-6 months of age due to maternal protection
57
HyperIgM syndrome
X-linked - Xq26
Failure of isotype switching
Detective CD40L gene , DC154
Basically means that activated T-cells cant chat to B-cells about what antibodies they need to make
elevated serum IgM, and undetectable IgA, IgE, IgG
58
Common variable immune deficiency
This presents with recurrent bacterial infections (often with severe end-organ damage), autoimmune disease, and granulomatous disease, as a result of low IgG, IgA, and IgE. The cause is unknown. It is a heterogenous group of disorders
59
Symptoms of IgE hypersensitivity
angioedema,urticaria, pruritus, rhinitis conjunctivitis,
| wheeze, diarrhoea, vomiting, and anaphylaxis
60
How long before skin prick test do you discontinue antihistamines?
48 hours
61
How do you investigate allergy?
Skin prick test (+ >2mm wheal)
Challenge test
During an acute episode - look for mast cell degranulation via mast cell tryptase levels (peak - 1 hr)
Component resolved diagnositics
Quantitative specific IgE to putative allergen (RAST)
62
What is component resolved diagnostics?
Measures IgE response to specific allergen protein
63
CRD - if patient is allergic to peanuts, what allergen protein is it?
Ara h2
64
What is the challenge test?
So you supervise them while they eat and see what happens (double blind - gold standard)
Risk of severe reaction
65
Define anaphylaxis
```
Severe hypotension
Laryngeal oedema
Difficulty breathing
Angioedema
Utricia
```
66
During anaphylaxis, when do you measure serum typtase levels?
1 hour, 3 hours and 24 hours
67
Mx of anaphylaxis
```
IM adrenaline 500 mcg
Oxygen
Inhaled bronchodilators
IV hydrocortisone 100mg
IV fluids
```
68
How much adrenaline is in an epipen?
300mcg for adults
| 150mcg for kids
69
Symptoms of allergic rhinitis
Nasal discharge, sneezing, loss of smell, nasal obstruction and itchiness, eye symptoms
70
What triggers allergic rhinitis?
Pets
Plants
Latex
71
Tx of allergic rhinitis
Oral histamines
Nasal corticosteriod spray
Monteleukast
72
Which cytokines are involved in allergy?
IL4, IL5, IL-10 (TH2)
73
Type 2 hypersensitivity?
IgM or IgG reacts with self-antigens. Usually of a specific tissue rather than systemic (antibody-mediated)
- Complement activation
74
How can you test for Type 2 hypersensitivity?
DAT (coombs) test
75
Examples of conditions which are type-2 hypersensitivity mediated?
```
Grave's disease
Haemolytic disease of the newborn
Autoimmune haemolytic anaemia
Goodpastures
Mysathenia Gravis
Wegener's granulomatosis
```
76
What is type III hypersensitivity?
Antibody-antigen complexes deposit in blood vessel walls and cause inflammation and damage
77
Difference between type II and type III hypersensitivity?
Complement activation is much greater in type III
Type II - antigen is not soluble whereas type III it is
Type II - more specific to tissue
Type III - more systemic
78
Examples of type III hypersensitivity reactions
SLE
Serum sickness
Polyarteritis nodosa - hep B
Mixed essential cryoglobulinaemia - assoc. hep c
79
What is type IV hypersensitivity?
T-cell mediated
80
Examples of type IV hypersensitivity?
```
Contact dermatitis
Mantoux test
RA
IBD
MS
TIDM + hashimotos (CD8)
```
81
HLA association for RA?
HLA DR4
82
HLA association for Ankylosing spondylitis?
HLA B27
83
HLA association for Goodpastures syndrome
HLA DR15 / DR2
84
HLA association for SLE
HLA DR3
85
HLA association for T1DM
HLA DR 3/4
86
HLA assocation for grave's disease
HLA DR3
87
Who is more likely to get sjorgen syndrome
Women
88
What is sjorgens syndrome?
Autoantibodies against the exocrine glands (tear and salivary glands)
89
Which antibodies are seen in sjorgens syndrome?
ANA +
Anti-Rho
Anti-La
90
Symptoms of sjorgen syndrome
Dryness of body surfaces
Keratoconjuctivitis - red, itchy eye with blurred vision
Ulceration and perforation of the nasal sputum
Infection prone
91
IPEX?
IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) is a rare disease linked to the dysfunction of the transcription factor FOXP3, widely considered to be the master regulator of the regulatory T cell lineage.
92
What HLA is associated with coeliac disease?
HLA-DQ2 or HLA-DQ8 (To eat or not to eight)
93
What antibodies are there in coeliac disease?
Anti-tissue transglutaminase antibody
Anti-endomysial antibody
Anti-Gliadin antibody
94
What do you see in coeliac disease histopathology?
Crypt hyperplasia
Villous atrophy
Lymphocyte infiltration
95
What skin manifestation is associated with coeliac disease?
Dermatitis herpetiformis
96
How can you boost the immune system?
Vaccination
Human normal immunoglobulin
Specific immunoglobulin (post exposure prophylaxis)
Recombinant cytokines
97
What kind of antibody class does Human normal immunoglobulin contain?
IgG against full range of organisms
98
Who receives human normal immunoglobulin?
Primary immunodeficiency where they cant make antibodies: SCID, Bruton's agammaglobulinaemia, CVID,
Secondary immunodeficiency where they cant make antibodies anymore : malignancy, bone marrow suppression
99
What conditions can you get post exposure prophylaxis
Hepatitis B
Tetanus
Rabies
Varicella zoster
100
What kind of recombinant cytokines do you give and to who?
Interferon-alpha: hep b, hep c, kaposi sarcoma, CML, hairy cell leukemia
Interferon-beta - relapsing MS
Interferon-gamma - chronic granulomatous disease
101
co-stimulation for T-cell activation
CD28 and B7
102
How does Ipilimumab work?
Stops the upregulation of CTLA-4 which stops the activation of T-cells so you get more T-cells
103
Who do we give Ipilimumab to?
Advanced melanoma
104
How does Pembrolizumab work?
specific to PD-1 and so stops upregulation and allows T-cells activation
105
How do we suppress the immune system?
- Non-specific immunosuppresion
- Remove the antibodies
- Target specific components of the immune response
106
What cytokine is involved with T-cell proliferation?
IL-2
107
How can we suppress T-cells before they meet APCs?
Anti-T-cell monoclonal antibodies
108
How do we suppress the proliferation of T-cells?
Corticosteriods
| Inhibitors of cell signalling
109
How do we suppress the effector function of T-cells?
Plasmapheresis
Corticosteriods
Anti-IL-12/IL-23 monoclonal antibody
110
Symptoms of an infusion reaction?
Ig-E type I hypersensitivity reaction
| Wheeze, hypotension, urticaria, headaches, fevers and myalgia
111
Why are corticosteriods immunosuppressive?
Inhibits phopholipase A2 and so inhibits arachidonic acid. Reduces prostagladin synthesis and so inhibits phagocytosis, expression of adhesion molecules
Increases apoptosis of lymphocytes
Decreases antibody production
112
How do cytotoxic drugs cause immunosuppresion
Inhibit DNA synthesis in rapidly dividing cells
113
Different types of cytotoxic drugs
Methotrexate
Azothioprine
Cyclophophamide
Mycophenolate
114
When do we use methotrexate and how does it work?
Used in ectopic pregnancy
RA
Crohns
Psoriasis
Mechanism - antifolate cos inhibits dihydrofolate reductase so inhibits DNA synthesis
115
When do we use aziothioprine and how does it work?
Used in autoimmune disease
Transplantation
Mechanism: anti-metabolite agent which stops the production of adenine and guanine. Metabolised in the liver to 6 mercaptopurine. Inhibits replication of DNA
116
When do we use cyclophosphamide and how does it work?
Anti-cancer agent
Vasculitis
Connective tissue disease
Mechanism: affects b-cells more than t-cells. Damages DNA by alkylating guanine and prevent cell replication
117
Who needs plasmapheresis?
Severe-antibody mediated disease like:
- Goodpastures
- Mysathenia
Antibody mediated rejection
118
Risk of plasmapheresis
Anaphylaxis
119
What drugs inhibit cell signalling?
```
Tacrolimus - IL-2 inhibitor
Sirolimus - blocks clonal proliferation of t-cells
Cyclosporin - IL-2 inhibitor
Tofactinib - JAK inhibitor
Apremilast - PDE4 inhibitor
```
120
What drugs are used in rejection prophylaxis in transplantation?
Tacrolimus and Cyclosporin
SE: nephrotoxic, hypertension, neurotoxic
121
What agents are directed at cell-surface antigens for immunosuppression
Rituximab - anti-CD20 (depletes mature B cells)
Abatacept - anti-CTLA4 (reduces T-cell activation)
Basiliximab - anti-CD25 (related to alpha chain IL-2)
Natalizumab - anti-alpha 4 integrin
Tocilizumab - anti-IL-6
Daclizumab - anti-IL2
122
Abatacept
Anti-CTLA4 (reduces T-cell activation)
123
Basiliximab
Anti-CD25 (related to alpha chain IL2)
124
Natalizumab
Anti-alpha 4 integrin (inhibits T-cell migration via VCAM1)
125
Tocilizumab
Anti-IL6
126
Daclizumab
Anti-IL2
127
Infliximab
Anti-TNF alpha
128
Golimumab
Anti-TNF alpha
129
Entanercept
TNF alpha/TNF beta
130
Denosumab
Anti-RANK ligand (bone SE) and used for bone malignany and osteoporosis
131
Which chromosome encodes HLA complex
Chromosome 6
132
Which HLA classes are on every cell?
HLA-CLASS I A, B, C,
133
Which HLA classes are just on APCs but can be upregulated on other cells in times of stress?
HLA-class DP, DQ, DR
134
When sel sel and her bestie got transplant, what was good about their HLAs?
Minimising HLA difference between donor and recipient improves transplant outcomes.
135
What is hyperacute transplant rejection? (mins-hours)
When the recipient has preformed antibodies that activate complement cascade
Thrombosis and necrosis
Tx: prevent via ABO groups crossmatching and HLA matching
136
What is acute-cellular transplant rejection? (weeks-mths)
CD4 activating a Type IV reaction
Tx: T-cell immunosuppression
137
What is acute-antibody mediated transplant rejection? (weeks - mths)
B-cell activation producing antibodies
Tx: plasmapheresis and B-cell immunosuppression
138
What is chronic transplant rejection? (mths-yrs)
Can be immune and non-immune
Risk factors:
- High BP
- Hyperlipidaemia
- Multiple acute rejections
Path: fibrosis, vasculopathy, bronchiolitis
Tx: minimise organ damage
139
GVHD (days-weeks)
Donor cells start fighting host
Symptoms: rash, D+V, bloody stool, jaundice
Tx: corticosteriods
140
When selena and her bestie went to get matched, what happened?
You need to determine the donors and recipient blood group and HLA type via PCR. Make sure they are v.similar
Check that the donor doesnt already have pre-formed antibodies against the donors HLA or ABO group via complement dependent cytoxicity, flow cytometry etc
Cross match them to make sure they dont react
After the transplant, check for new antibodies
141
How does haematopoietic stem cell transplant work?
- Eliminate hosts immune system via total body irradiation or cyclophophamide
- Replace with new bone marrow
142
What are post-transplant complications?
- immunosuppressed so more likely to get oppurtunistic infections
- Increased risk of malignancy - esp viral associated such as EBV (lymphoproliferative disease), HHV8 (kaposi sarcoma)
- Atherosclerosis
143
Isograft
Transplant from twin
144
Allograft
from same species (human)
145
Xenograft
from different species
146
Split graft
shared by two recipients
147
How does HIV bind to CD4 cells?
GP120 + GP41 and co-receptor CCR5 + CXCR4
148
What type of virus is HIV?
single stranded RNA retrovirus
149
What enzyme does HIV use?
reverse transcriptase (converts RNA --> DNA)
150
How does HIV affect CD8 T-cells?
- Infected CD4+ T cells are also anergised by the virus,
meaning CD8+ cellscannot be primed, and CD4+ and CD8+ responses are greatly diminished
- Infected macrophages and dendritic cells are killed by the virus, leading to defects in antigen presentation, and failure to activate memory responses.
151
Steps in viral replication
```
Attachment/Entry
Reverse transcription and DNA synthesis
Integration
Viral transcripton
Viral protein synthesis
Assembly of virus and release of virus
Maturation
```
152
What is the innate immune response to HIV?
Non-specific activation of macrophages, NK cells and complement
Stimulation of dendritic cells via TLR
Release of cytokine and chemokines
153
What is the adaptive response to HIV?
Neutralising antibodies: Anti-GP120 and anti-GP41
Non-neutralising antibodies: anti-pg24 gag IgG
CD8 tcells secrete chemokines MIP-1a, 1b and RANTES
154
How does HIV damage the immune system?
- HIV remains infectious even when Ab coated
Activated infected CD4+ helper T cells are killed by CD8+ T cells
Activated infected CD4+ helper T cells are anergised (disabled)
CD4 T-cell memory lost & failure to activate memory CTL
Monocytes and dendritic cells are therefore not activated by the CD4+ T cells and cannot prime naïve CD8+ CTL (due to impaired antigen presenting functions)
Infected monocytes and dendritic cells are killed by virus or CTL
Quasispecies are produced due to error-prone reverse transcriptase = these escape from immune response
Effective immunity requires antibodies to prevent infection and neutralize virus, and sufficient CTL to eliminate latently infected cells
155
Shit i think i have HIV, how do i get diagnosed?
Screening : anti-HIV ab via ELISA
Confirmation: Western blot detects ab
This must be done 10 weeks post exposure due to seroconversion
156
How are HIV patients monitored?
Viral load - via PCR
CD4 count - via flow cytometry
AIDs - less than 200 CD4 count
157
Tx of HIV
HAART
Pregnancy- Zidovudine (oral during pregnancy, IV during labour) and give to baby for 6 weeks
158
Vaccination schedule
https://memorize.com/uk-vaccination-schedule/michaelokocha
159
Memory T-cells
CD45 RO
160
Naive T-cells
CD45 RA
161
Where are central memory cells found (CCR7+)
Lymph nodes and tonsils
162
What do central memory cells produce
IL-2
163
Where are effector memory cells found (CCR7-)
Liver, lungs and gut
164
What do effector memory cells produce
INF-gamma and perforin
165
CCR7?
- CCR7 binds CCL19 and CCL21 present on the luminal surface of endothelial cells in lymph nodes which causes firm arrest and the initiation of extravasation.
CCR7 directs homing of dendritic cells to lymph nodes
CD62L interacts with a molecule on HEV, which mediates attachment and rolling
166
B-cell memory
B cells stimulated by antigen -> expansion/isotope switching (due to cytokines provided by T helper cells) -> plasma cells producing antibody/memory cells
Memory cells that can differentiate into plasma cells (long lived)
These cells produce: Quicker response, more antibodies, higher affinity antibodies,
more IgG and generally better antibodies.
167
TH1
IL-12, IFN-gama and TNF
168
TH2
IL-4, 5, 6
169
Which cytokine is the first to be released during initial exposure to the allergen
IL-12
170
CH50 and AP50 tests
complement deficiencies
171
Tx for wegener's g
Corticosteroids,
cyclophosphamide
co-trimoxazole
172
Tx for chaug-strauss syndrome
Prednisolone,
Azathioprine,
Cyclophosphamide
173
Tx for goodpastures and pemphigus valigarus
Corticosteroids and immunosuppression
174
Mixed Essential Cryoglobulinaemia
Associated with Hep C antigens - IgM and IgG
175
↓C4
SLE
176
Tx of MS
Corticosteroids,
| Interferon-β
